SELS ACIDES DE L'ACIDE VALPROIQUE

ACID SALTS OF VALPROIC ACID

Abrégé anglais

ACID SALTS OF VALPROIC ACID
Abstract of the Disclosure
The calcium salt of valproic acid having the
<IMG>
The salt of the invention is useful in the treatment of
epileptic seizures, and can be conveniently formulated
into oral dosage forms.

Revendications

WHAT IS CLAIMED IS:
1. A process for preparing a compound having the
following formula:
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wherein n is 2 to 20,
which comprises reacting one mole of Ca(OH)2 with four moles
of valproic acid and recovering the desired compound.
2. A compound having the following formula:
<IMG>
wherein n is 2 to 20.

3. An oral pharmaceutical dosage form containing,
as the principal active compound, a compound of the formula:
<IMG>
wherein n is 2 to 20, and a pharmaceutically acceptable
diluent.

Description

~ackground of ~he Invention
.
This invention relates to valproate salts, and
more particulacly to certain alkali metal salts of
valproic acid having improved stability.
~ alproic acid or 2-propylpentanoic acid has
come into wide-spread use in the treatment of epileptic
seizures or convulsions, ~ost commonly used are
valproic acid and its sodium salt; the acid is a liquid
while the sodium salt is a hygroscopic solid
characterized by poor stability. AS a result, both have
limited utility in the preparation of oral dosage forms.
Significant improvements in the forms of
valproic acid-salts have been achieved as described in
Canadian Patent 1~136,151. As described in those
applications, it has been found that highly stable,
non-hygroscopic compounds derived from valproic acid
can be prepared from equimolar amounts of (a) valproic
acid or diethylacetic acid and (b) a valproate salt of
sodium or calcium.
It has been discovered that some of the
compounds thus produced are in the nature of an
oligo~er. For example, the compound formed from
valproic acid and sodium valproate has t~ structure:
_ ~ 3H7 C3117 C3H7y C3H7
~c~ Q ~ o~C~oH (I)
~ ~: }~~c~
-- C3H7J~ C3H7 C3H7 C3H7 ' n
The polymer contains about 2 to 20, preferably from
about 4 ~o 12 and most preferably about 8 o ~he
repeating units.
.,~, ~

3~
A comparison of infrared spectra and ~-ray
diffraction patterns of sodium valproate, valproic acid
and the sodium complex reveal that the above complex (I)
is a chemical entity and not a mixture of the two
precursors. Without limitation as to theory, the outer
shell of electrons of the sodium atom is filled by
coordination to the oxygen atoms of both valproic acid
and valproate ions, resulting in a stable complex in
which the sodium ion is completely surrounded by oxygen.
The calcium salt formed when use is made of a
mole ratio of valproic acid and valproate salt is a
monomeric salt whicn has the structure:
O ~ CH 2 2 3
CH2CH2C~l3
CH3CH2Ci~2 ~P C ~ ~ ,_~ CH2CH2 3
CH CH CH >~ `o9 // CH2cH2cH3 ( II)
C~cH2cH2cH3
CH2CH2CH3
Thus, as described in the foregoing application, one
mole oE valproic acid and one mole of valproate salt are
coordinately bonded to one-half of a calcium atom.
It has now been found that an oligomeric
calcium salt of valproic acid can be Eormed with four
moles of valproic acid complexed with a calcium ion.
Without limiting the invention as to theory, it is
believed that the oligomeric salt has the structure:
l C 2 C 2 3
CH CH C}l HO e, (III~
3 2 2tC~P 0~ ~ _~ CH2CH2CH3
CH3CH2CH2 OH CH2CH2CH3
~C~ 2 2 3
CH2CH2C~3 _ n

--3--
Thus, unlike the monomeric complex formed by
the association of one mole of valproic acid and one
mole of calcium valproate, the salt of the present
invention is oligomeric.
The compound of the present invention is a
distinct chemical entity, crystalline in nature and has
well defined physical and chemical properties.
The calcium salt of the present invention can
be prepared by reacting one mole of calcium hydroxide
with four moles of valproic acid in a~ueous media, and
then removing the water to recover the crystalline
complex thus produced. As will be appreciated by those
skilled, the inclusion of small amounts of other Eatty
acids such as diethylacetic acid does not materially
alter the complex thus produced in that it simply
replaces one or more moles of valproic acid with a
biologically inactive acid.
The resulting complex is thus formed of two
moles of the alkali metal valproate and two moles of
valproic acid. The salt is useful in the treatment of
epileptic seizures or convulsions, and can conveniently
be forlnulated in solid dosage forms, either alone or in
combination with one or more phaemaceutically ac~eptable
diluents in accordance with U.S. Patent No. 3,3~5,361.
Typical diluents or excipients include starch, talcum
powder, lubricants, disintegrators, flavoring agents,
coloring agents or the like.
When used herein in the treatment of e~ileptic
seizures or convulsions, the compounds and compositions
of the present invention should be ad~i~istered in an
amount of from 1 to 100 mg/kg body weight~day,
preferably 1~ to ~4 mg/kg body weight/day ~f valproic
acid.
Having described the basic concepts of the
invention, reference i5 now made to the following

7~
examples which are provided by way of illustration and
not by way of limitation, of the practice of the
invention.
Example
This example illustrates the preparation of the
calcium salt of valproic acid.
One mole of Ca(OH)2 (74.08 g) was dissolved
in 100 ml of water in a 500 ml volumetric flask equipped
with a stirrer and heating mantle. Four moles of
valproic acid (576.84 g) were added and the resulting
mixture stirred and heated to bo~ling.
The water was distilled off over a period of
approximately 2 hours, and the residue in the flask
solidified. That solid was isolated and dried by
dissolving in hexane, drying over anhydrous sodium
sulfatet filtering and then evaporating the hexane.
The compound obtained has the structure:
o~ ,~ CH 2 2 3
l CH2CH2C 3
CH3CH2CH2 ~ 0~ ~ CH2C~12CH3
CH3CH2CH2>~ CH2CH2C 3
2 CH 2 CH 3
CH2CH2CH3 _ n
It will be understood that various changes and
modifications can be made in the details of procedure,
formulation and use without departing from the spirit of
the invention, especially as defined in the following
claims.